tbuckley/cabot-search huggingface dataset:
Influence of age, sex and tumor type in the likelihood of inclusion in early clinical trials.
Authors: Maria Vieito, Katerin Ingrid Rojas, Roger Berché, Cristina Viaplana, Julia Lostes, Vladimir Galvao, Guzman Alonso, Honey Kumar Oberoi, Irene Brana, Mafalda Oliveira, Macarena González, Enriqueta Felip, Cristina Saura, Joan Carles, Teresa Macarulla, Elena Garralda, Josep Tabernero, Omar Saavedra
Journal: Journal of Clinical Oncology (2023)

e15193 Background: Inclusivity in early drug development is essential for achieving consistent and accurate results. Sex-specific differences in biology and pharmacology should be explored as early as possible during clinical development. Lack of inclusion of elderly patients underestimates the risk of toxicity due to comorbidities and polypharmacy, but adolescents and young adult patients (AYAs) are even less represented in clinical trials, leading to slower improvements in survival. Methods: Patients referred for a first consultation to Vall de Hebron Institute of Oncology Early Drug Development Unit between 2019-2021 were analyzed. Clinical variables included: age, sex, primary tumor location, clinical trial inclusion and type of clinical trial. Results: On a total of 1218 pts, a total of 580 (48.53%) were included in at least 1 early clinical trial. The median age of the overall population was 61 y(ranging from 22 to 92), with no differences in pts included (62y) or not(60y) in clinical trials. Elderly patients ( &gt; 75y) were 9.1% of the population referred and achieved a similar rate of inclusion (46.90% vs 49.44%) while AYAs(18 to 29-year-old) represented only 1.47% of pts referred and were only matched to a clinical trial in 33.33% of cases. (Fisher’s p-value = 0.06). Equal proportion of males and females were referred to clinical trials, with the exception of elderly patients (60.17% male) and AYAs(61.11%). the overall population). In the overall population the most common primary tumor locations were colorrectal (24.38%), other gastrointestinal tumors (18.14%) and breast cancer (10.91%). The most common primary tumor location in patients &gt; 75y was colorectal(28.82%), other gastrointestinal tumors(19.81%) and head and neck(14.41%) vs sarcoma(38.88%), CNS(27.77%) and other gastrointestinal(11.1%) in AYA patients. Inclusion rates depending on the type of tumor ranged from 63% to 23%. Patients with genitourinary and gynecologic cancers had a statistically significant higher likelihood of being included in a clinical trial whereas sarcoma and primary CNS tumors had lower chances of being included in a clinical trial. In a binomial multivariant model the only factor predictive of inclusion in a early clinical trial was tumor type, whereas, sex, age group and availability of molecular profiling, was not statistically significant. Conclusions: Elderly patients with cancer and AYAs were referred less frequently to our unit that the overall prevalence of cancer in those populations and in the case of AYA pts the rate of inclusion lagged behind, driven mainly by the tumor types more common in each population.
Utilize protein markers and genomic features for minimal residual disease detection in hepatocellular carcinoma.
Authors: Shichun Tu, Shiyong Li, Qingqi Ren, Guolin Zhong, Yunfei Li, Yumin Feng, Yixia Zhang, Yinyin Chang, Guanghui Long, Dandan Zhu, Shuaipeng Geng, Mao Mao
Journal: Journal of Clinical Oncology (2023)

e15054 Background: Several studies have shown the clinical value of using circulating tumor DNA (ctDNA) for minimal residual disease (MRD) detection, which is more sensitive than traditional imaging methods. However, most MRD detection technologies focus on identifying mutations and require cancer tissue samples. These methods often have limitations, such as high cost, inaccessible cancer tissue, or inability to overcome tumor heterogeneity. SeekInCure is a cost-effective multi-dimensional MRD test that does not require cancer tissue analysis. The purpose of this prospective study was to evaluate the potential broad clinical utility of SeekInCure for detecting MRD in patients with hepatocellular carcinoma (HCC). Methods: 34 HCC patients undergoing radical surgery were prospectively enrolled in this study from Peking University Shenzhen Hospital. Peripheral blood samples of 8 mL were collected before and after surgery and analyzed using the SeekInCure assay, which integrates the protein tumor marker (AFP) and cancer genomic hallmarks: copy number aberrations and fragment size from ctDNA. Patients with positive results for AFP and/or ctDNA in the preoperative/postoperative samples were defined as MRD-positive (MRD+), while negative results were defined as MRD-negative (MRD-). Results: Of the 34 patients, 73.5% (25/34) were in early stages (stages I/II: 61.8%/11.8%), and 61.8% (21/34) received adjuvant therapies. The median follow-up was 279.5 days, ranging from 90 to 1,253 days. 82% (28/34) of the patients had MRD+ results in the preoperative samples, which showed remarkable sensitivity in a cohort with more than 70% of early-stage patients. Our previous findings were confirmed, with preoperative MRD+ patients having worse survival than MRD- patients 1 . After radical surgery, 26.5% (9/34) were MRD+. MRD+ patients had worse survival than MRD- patients, with a median overall survival (OS) time of 298 days for MRD+ patients, while the OS time for MRD- patients was not reached (P &lt; 0.01). 6 patients with MRD- in both pre- and post-operative samples had a very favorable outcome (100% OS). Conversely, 9 patients with both positive results had the worst outcome. We also found that MRD- patients receiving adjuvant therapies did not have a survival benefit compared to those without adjuvant therapies, but MRD+ patients receiving adjuvant therapies had better OS than those without adjuvant therapies (P = 0.026). Conclusions: This study confirms the excellent performance of our SeekInCure assay, which does not require cancer tissue analysis, in detecting MRD and the prognostic value of MRD in HCC patients. Adjuvant has no influence on survival, especially in MRD- patients, which indicates that amost one-third of HCC patients do not need additional adjuvant therapy.
The impact of hispanic ethnicity in presentation and outcomes of patients with synovial sarcoma.
Authors: Priscila Barreto Coelho, Caroline Hana, Natalia Yanchenko, Steven Bialick, Andrew Rosenberg, Aditi Dhir, Emily Jonczak, Gina Z. D'Amato, Atif Mahmoud Hussein, Jonathan C. Trent
Journal: Journal of Clinical Oncology (2023)

e18682 Background: Synovial sarcomas (SS) harbor a specific, balanced, reciprocal translocation t(X;18) leading to the oncogenic SS18-SSX fusion. It accounts for 5-10% of all soft tissue sarcomas, and there is a lack of information regarding the impact of race and ethnicity on its presentation and outcomes. Florida is currently not included in the SEER database, and it is the US's ninth-most diverse population, with a diversity index of 64.1% and with the sixth-highest Hispanic population among all states. Sylvester Comprehensive Cancer Center (SCCC) and Memorial Healthcare System (MHS) are two large oncology centers in South Florida that provide care for this rare type of tumor. We aimed to identify the impact of Hispanic ethnicity in SS. Methods: We retrospectively reviewed all patients with a confirmed diagnosis of SS between January 2003 and January 2022 in SCCC and MHS. All data were retrieved from electronic medical records. SPSS Statistics was utilized, Fisher exact test and log-rank test were used for analysis. A two-sided p &lt; 0.05 was considered statistically significant. Results: A total of 73 patients had a pathologically confirmed diagnosis of SS, with information regarding ethnicity, during the time period evaluated, 45.3% were Hispanic, and 54.7% were non-Hispanic. The Hispanic group was comprised mainly of female patients (66%) with a median age of diagnosis of 44 years old, these findings were similar in the non-Hispanic group, where 55% were women, and the median age at diagnosis was 42 years old. Fewer patients identified themselves as Black within the Hispanic group (3%) compared to the non-Hispanic (22%) (p = 0.016). The most common site of primary disease was the extremity in both groups (Hispanic 63% vs non-Hispanic 75%) (p = 0.384). Most tumors were diagnosed with a size bigger than 5cm (Hispanic 57% vs non-Hispanic 65%) (p = 0.577) and with pathology reporting a monophasic SS (Hispanic 45% vs non-Hispanic 50%) vs biphasic or poorly differentiated (p = 0.061). Non-Hispanics had more poorly differentiated tumors (Hispanic 3% vs non-Hispanic 17.5%) (p = 0.054). Hispanic patients did have fewer cases of metastatic disease at diagnosis (Hispanic 9% vs non-Hispanic 32%) (p = 0.023). The median overall survival (mOS) among Hispanic patients was not reached in our study, and mOS among the non-Hispanic patients was 5 years (p = 0.099). Conclusions: In our study, the patients more commonly presented with large tumors ( &gt; 5cm) in the extremity and monophasic histology, regardless of their ethnicity. Non-Hispanic patients more often had poorly differentiated tumors, metastatic disease at diagnosis, and a trend toward worse mOS. This study had limited power due to the limited number of patients, and further studies are needed to identify the presence of disease-related differences in these populations.
Pattern of CD8<sup>+</sup> tissue resident memory T cells between local recurrence and distant metastasis in nasopharyngeal carcinoma.
Authors: Ngar Woon Kam, Cho Yiu Lau, Syrus Pak Hei Lai, Chi Ming Che, Victor Ho-Fun Lee
Journal: Journal of Clinical Oncology (2023)

e15161 Background: CD8 + T lymphocytes are believed to be the major anti-tumor immune subsets. Consequently, most cancer immunotherapeutic approaches seek to amplify cytotoxic T lymphocytes specific to malignant cells. A recently identified subpopulation of memory CD8 + T cells, named tissue-resident memory T (Trm) cells, persists in non-lymphoid tissues, including solid tumors. This T-cell subset is considered an independent memory T-cell lineage with cytotoxic features. However, their function, spatial location and influence on disease-related outcomes (local recurrence [LR], distant metastasis [DM] in nasopharyngeal carcinoma (NPC), a disease entity characterized by substantial immune infiltrate, remain poorly understood. We aim to close this gap through investigation on the abundance and spatial localization of CD8 + Trm in relation to tumor site (primary or recurrence [LR and DM]). Methods: This retrospective cohort analysis based on 20 NPC patient samples: primary (initial diagnosis; [I; n = 19], recurrence ([LR; n = 14] and [DM; n = 10]). We accessed the spatial localization in tumor tissues within tissue-segmented classifications of either cancer islands (pan-cytokeratin–positive [CK+] areas) or stromal areas (CK– areas). Tumor infiltrating lymphocytes (TILs) among patients from I, LR and DM group was quantified through multiplexed 5-colour opal staining using biomarkers against CD8, CD103, IL17, CK plus DAPI (nuclear cell counterstain). Results: While total CD8 + TILs (total tumor) as well as their spatially localized cell densities (tumor islet [TI] vs. tumor stroma [TS]) did not show any significant changes among I, LR and DM patient groups, a higher proportion of CD8+ TILs in the TI co-express the CD103 molecule, an indication of CD8+ Trm (CD103+CD8+) infiltration (mean CD103 + CD8 + /CD8 + in TI: 32.1% in I group, 44.8% in LR group, 46.0% in DM group; mean CD103 + CD8 + /CD8 + in TS: 19.0% in I group, 26.2% in LR group 26.2% in DM group). Notably, we observed that such augmentation only reached statistically significant within TI from patient in LR group (p = 0.0451). Furthermore, we found that CD8+ Trm in the LR group expressed higher level of cytokine IL-17, which was ~2.1-fold (p = 0.0788) and 3.6-fold upregulated (p = 0.0285) as compared to I and DM, respectively. Conclusions: Cancer islet–localized CD8 + TILs are composed of CD103 + Trms, which make up nearly 45% the total CD8 + T cell population within LR tumors of NPC patients, highlighting spatial localization of CD103 + CD8 + Trms as a key phenotype of CD8 + TIL subset. The CD8 + Trm expressed with increased IL17 suggests that enrichment of this T-cell subset might exerts cytotoxic functions. Our results demonstrate that CD8 + Trm had a greater likelihood as an indicator of LR risk for NPC patients and help identify patient cohorts likely to benefit from immunotherapy.
Efficacy and safety of IBI110 in combination with sintilimab and lenvatinib in first-line of advanced hepatocellular carcinoma: Preliminary results from a phase Ib study.
Authors: Ming Liu, Kun Wang, Quan Bao, Hongwei Wang, Kemin Jin, Wei Liu, Jia Luo, Nong Xu, Tao Zhang, Yongxiang Xia, Guoliang Shao, Baorui Liu, Jie Shen, Haonan Chen, Sixiang Long, Yuling Chen, Li Zhao, Hongli Wang, Baocai Xing
Journal: Journal of Clinical Oncology (2023)

2577 Background: Sintilimab plus bevacizumab has been approved as first-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC). Dual inhibition of PD-1 and lymphocyte-activation gene 3 (LAG-3) may improve anti-tumor effect synergistically. IBI110 plus sintilimab has shown preliminary antitumor activity in advance solid tumors. This phase Ib cohort study evaluated the efficacy, tolerability, and safety of IBI110 in combination with sintilimab and lenvatinib as first-line treatment in pts with advanced HCC. Methods: This phase Ib study enrolled pts with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment. Patients received IBI110 200mg IV Q3W and sintilimab 200mg IV Q3W, in combination with lenvatinib (weight &lt;60kg: 8mg, weight ≥60 kg: 12mg) orally administered once daily, until disease progression, unacceptable toxicity or death. The primary objective was to evaluate the safety, tolerability, and efficacy of the combination therapy per RECIST v1.1. Results: As the data cutoff date on January 9 th 2023, 28 pts were enrolled (median age: 59 years; ECOG PS=0: 6 pts; stage C per Barcelona Clinic Liver Cancer [BCLC]: 13 pts). All 28 pts were included for safety analysis. Treatment-related adverse events (TRAEs) of any grade occurred in 27 pts (96.4%) and the most frequent TRAEs included hypertension (50%), hypothyroidism (42.9%), neutrophil count decreased (39.3%). Grade ≥ 3 TRAEs occurred in 16 pts (57.1%) and grade ≥3 irAEs occurred in 4 (14.3%) pts. Two (7.1%, 2/28) pts experienced TRAE leading to drug discontinuation. One pt experienced investigator-assessed treatment related death. As of data cutoff, for 27 pts with at least one efficacy evaluation, the objective response rate (ORR) was 29.6% (95% CI, 13.8-50.2). The disease control rate (DCR) was 85.2% (95% CI, 66.3-95.8), and 11 pts were still in treatment. With a median follow up of 12.2 months (95%CI, 11.0-12.6), the median progression-free survival (PFS) was 9.9 months (95%CI, 5.7-NC) and the 9-month PFS rate was 54.5% (95%CI, 33.8-71.2). The median overall survival (OS) was not reached. Conclusions: In this phase Ib study, IBI110 in combination with sintilimab and lenvatinib as first line therapy demonstrated robust response and survival benefit with manageable safety profile in patients with advanced hepatocellular carcinoma. This combination therapy need to be further explored in this population. Clinical trial information: NCT04085185 .
A phase II study cohort of penpulimab plus anlotinib in patients with recurrent or metastatic non-squamous cell carcinomas of head and neck.
Authors: Changgong Zhang, Yan Sun, Jun Wang, Zhigang Liu, Haichuan Su, Jianhua Chen, Youxin Tian, Huijuan Wu, Liying Gao, Yuankai Shi
Journal: Journal of Clinical Oncology (2023)

e18013 Background: Recurrent or metastatic non-squamous cell carcinoma of head and neck (R/M non-SCCHN) lack effective systemic treatment. The feasibility of the combination of immune checkpoint inhibitor and anti-angiogenic agents in the treatment of R/M non-SCCHN was unknown. Penpulimab is a novel anti-programmed cell death-1 (PD-1) antibody with complete elimination of FcγR binding activity. Anlotinib is a multi-kinase inhibitor blocking angiogenesis and tumor cell proliferation simultaneously. ALTN-AK105-II-01 is a single-arm, multi-cohort, multi-center phase II study to investigate the efficacy and safety of penpulimab plus anlotinib in the treatment of various advanced cancers. Here we report the results of the cohort 2 for patients (pts) with R/M non-SCCHN. Methods: Eligible pts were aged 18 years or older and diagnosed with histologically confirmed R/M non-SCCHN. Other inclusion criteria included ECOG PS 0-1 and having at least one measurable lesion according to RECIST 1.1, and anti-angiogenic agents or immune checkpoint inhibitor treatment-naïve. Pts were given penpulimab 200mg intravenously on day 1 and oral anlotinib 12mg once daily from day 1 to day 14 every 3 weeks until disease progression or unacceptable toxicities. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: From May 21, 2020 to October 14, 2020, 21 pts were enrolled in 7 centers in China. The most common site of primary tumor was salivary gland (15/21, 71.4%) and the most common pathological types included adenoid cystic carcinoma (7/21, 33.3%) and duct carcinoma (4/21, 19.0%). 15 pts (71.4%) had distant metastatic lesions and 12 pts (57.1%) had prior chemotherapy history. As of October 20, 2022 (data cut-off), 4 pts achieved confirmed partial response and the ORR was 19.0%. Stable disease (SD) was observed in 17 pts and the DCR was 100%. The median follow-up for PFS was 14.2 months (95%CI: 7.8, 20.6), 9 pts suffered disease progression and the median PFS was 10.6 months (95%CI: 0.0, 22.4). 14 pts (66.7%) experienced at least one ≥grade 3 treatment-related adverse events (TRAEs) and the most common ≥grade 3 TRAEs was hypertension (15.0%). No treatment-related death was reported. Conclusions: The combination of penpulimab and anlotinib showed encouraging efficacy and favorable safety profile in R/M non-SCCHN and is worthy of further investigation. Clinical trial information: NCT04203719 .
Biliary intervention combined with lenvatinib+ PD-1 inhibitor of Klatskin tumor complicated with malignant obstructive jaundice.
Authors: Xiaobo Fu, Maoyuan Mu, Han Qi, Weiwei Jiang, Zixiong Chen, Fei Gao
Journal: Journal of Clinical Oncology (2023)

e14620 Background: Hilar Cholangiocarcinoma (Klatskin tumor) is a rare and highly aggressive cancer that occurs at or near the junction of the right and left hepatic ducts. Gemcitabine + cisplatin has been established as an effective first-line treatment. However, this malignancy is commonly complicated by malignant biliary obstruction which may gradually damage patients’ liver function and may limit the chemotherapy. In addition, Cumulative clinical evidence showed that tyrosine kinase inhibitor (TKI) combined with immunotherapy is represented as a promising alternative. This study aimed to evaluate the clinical value of biliary intervention combined with the Lenvatinib+PD-1 inhibitor (Tislelizumab/Sintilimab) for the Klatskin tumor. Methods: From January 2020 to December 2022, 21 Klatskin tumor patients with malignant hilar biliary obstruction (MHBO) were included. All included patients received biliary decompression by metal stent + Iodine-125 seed strand (ISS) implantation. The number of 125I seeds to be implanted was determined according to the plan of the preoperative computerized treatment planning system (TPS). The procedure-related outcomes were evaluated regarding successful drainage and complications. In addition, the survival of patients who received successful biliary drainage and patients who received sequential systemic anticancer treatment were analyzed. Successful biliary drainage was defined as the serum total bilirubin level dropped by 75% of the preoperative value within 4 weeks. Major complications referred to those that result in death or serious adverse effects including sepsis, uncontrollable biliary or intestinal bleeding, and acute renal failure. The time between stent insertion and death was defined as patient survival. Results: 71.4% achieved successful drainage, significant improvements were observed from before to one month after the procedure in liver function values, including total bilirubin (TBIL), and direct bilirubin (DBIL) (all P&lt;0.001). Minor complications occurred in 5 patients (23.8%) in all patients, including 1 patient (4.8%) who experienced cholangitis, and 4 patients (19%) who suffered abdominal pain. No major procedure-related complication was observed. The median overall survival(mOS) of 21 patients was 6.1 months. Patients who received successful biliary drainage (n=15) had longer mOS than those who received unsuccessful biliary drainage(n=6) [7.4 months vs. 3.5 months, respectively, P&lt;0.001]. Patients who received sequential Lenvatinib+ Pembrolizumab after effective drainage(n=9) had longer mOS than those who only received palliative therapy(n=6) [7.4 months vs. 5.2 months, respectively, P=0.028]. Conclusions: Biliary intervention + ISS combined with the following Lenvatinib+ PD-1 inhibitor is safe and feasible for cholangiocarcinoma patients complicated with obstructive jaundice.
Proposition of a drug score to predict the clinical usefulness of therapeutic dose monitoring of oral molecularly targeted therapies.
Authors: Arthur Geraud, David Combarel, Christian Funck-Brentano, Quentin Beaulien, Noel Zahr, Sophie Broutin, Christophe Massard, Benjamin Besse, Paul Gougis
Journal: Journal of Clinical Oncology (2023)

3091 Background: Therapeutic drug monitoring (TDM) consists in measuring and interpreting drug concentrations in biological fluids to personalize drug dosage. This method is widely used for drugs with a narrow therapeutic index ( e.g., immunosuppressants or neuroleptics agents). In onco-hematology, current recommendations of TDM for oral molecularly targeted therapies (oMTT) differ among molecules, making it difficult to identify good TDM candidates. This study aims to propose a quantitative approach with a score to predict the clinical usefulness of TDM of oMTT. Methods: We selected the four key parameters needed for an oMTT to be a good candidate for TDM (e.g. interpatient pharmacokinetic variability, feasible dose-adaptation strategy, exposure-efficacy relationship, exposure-safety relationship). We collected each drug’s pharmacokinetic (PK) and pharmacodynamics variables from drug labels, Center for Drug Evaluation and Research reports and early trials data. The score was defined from oMTT’s exposition variability (variability score: coefficient of variation of drug exposition, the impact of food and proton pump inhibitors), technical complexity (PK linearity, active metabolite, half-life), efficacy (Exposure-response relationship (ERR)) and safety (maximum tolerated dose, Exposure-safety relationship (ESR)). The global score ranged from 0 to 100. To assess the relevance of the score, we evaluated molecules from other therapeutic classes with known strong recommendations of TDM (clozapine, everolimus, voriconazole). Results: In September 2021, we collected data from sixty-seven oMTTs. Scores were normally distributed (mean 48.3, standard deviation 15.6) and varies from 15 for acalabrutinib to 80 for sunitinib. Scores of drugs with strong recommendation of TDM were 68, 68 and 64 for clozapine, everolimus as an immunosuppressant, and voriconazole, respectively. We hypothesized that a score above 60 might be associated with relevant indications of TDM. Fifteen molecules had a score above 60 (sunitinib (80), cabozantinib (76.5), nilotinib (76), abemaciclib (76), axitinib (75), sorafenib (69.5) gefitinib (69.5), trametinib (67.5), talazoparib (67), crizotinib (66), pazopanib (65), sonidegib (63.5), neratinib (62.5), panobinostat (62) and imatinib (60.5)). Conclusions: We defined a score to identify good candidates for TDM in onco-hematology. Usefulness of TDM in oncology should be confirmed prospectively prioritizing these molecules.